Abstract Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disorder with protean manifestations. The HLA complex in general and HLA-DR in particular remains the most dominant genetic risk factor for disease susceptibility. A striking feature is the strong association of autoantibody specificities with some HLA haplotypes. This proposal addresses the mechanisms for this close association. In this proposal we will test the hypotheses that in lupus patients, molecular mimicry with microbial peptides is responsible for the selective enrichment of T cells reactive with lupus-associated auto antigens. Depending on microbial exposure, the HLA dictates the nature of cross-reactive peptides it binds and thereby the auto antigen selection. This process leads to activation of self-reactive T cells, autoantibody production, epitope spreading and end organ damage. Using SmD as the candidate auto antigen and HLA-DR3 (DRB1*0301) transgenic mice and HLA-DR3 positive SLE patients, following specific aims are proposed 1) To demonstrate that multiple exposures to peptide mimics of SmD T cell epitopes influence the SmD reactive T cell repertoire 2) To determine the pathogenic potential of anti- SmD initiated autoimmune responses in lupus-prone NZM2328 mice transgenic for HLA-DR3 3) To investigate the ability of HLA-DR3 restricted SmD peptide mimics to activate T cells from HLA- DR3 positive SLE patients 4) To demonstrate that SmD reactive T cell repertoire is different in SLE patient populations from distinct geographical areas using lupus patient cohort from Mayo Clinic, Minnesota and Charlottesville, Virginia. The findings from this proposal will clearly demonstrate that T cell responses to lupus-associated antigens can initiate autoimmune responses in SLE patients with HLA-DR3. This will provide a theoretical framework from which rational therapeutic approach can be devised for treatment and prevention of SLE.